The broad long term goal of this project is to empower women to protect themselves from HIV infection through the development of improved microbicides based on our clinically proven sustained release technology platform. Using this platform drug delivery devices for a broad range of drugs have been approved by the FDA and are in current clinical use. The ganciclovir intraocular implant: the Vitrasert(r), approved for the treatment of AIDS related CMV retinitis releases the relatively soluble antiviral ganciclovir into the eye for a period of eight months. The Retisert(r) releases the relatively insoluble steroid fluocinolone acetonide for up to three years. We propose to utilize this platform to develop sustained release vaginal ring microbicide formulations for the antiretroviral agents tenofovir and TMC 120. In the first two years of this project (R21) we will evaluate the hypothesis that, when incorporated into a ring formulation, the prodrug tenofovir disoproxil fumarate is superior to the parent drug tenofovir as candidate microbicide. In the second phase of the project (R33) we will manufacture and test ring formulations containing multiple antiviral agents. We hypothesize that, using our unique drug delivery platform, there will be no loss of elution characteristics with the incorporation of multiple drugs into our system. The successful completion of this project will result in the submission of an investigational new drug exemption (IND) leading to clinical trials for these formulations. Each day 15,000 people are infected by HIV, the majority in sub-Saharan Africa and a growing percentage women infected though heterosexual sex. The broad long term goal of this project is to empower women to protect themselves from HIV infection through the development of improved vaginal ring formulations for microbicides based on the sustained release drug delivery of antiviral agents. Our clinically proven sustained release drug delivery platform uniquely allows us to deliver drug of both high and low aqueous solubility. We propose to utilize this platform technology to develop long-term vaginal ring formulations for the potential microbicides tenofovir and TMC-120.